Multiresistant tuberculosis is defined as that tuberculosis which is caused by strains of Mycobacterium tuberculosis resistant simultaneously to at least isoniazid and rifampicin. Its incidence has increased in the last number of years in an alarming rate in a numerous regions in the worldwide. The importance of this problem is illustrated in the decision taken by the WHO in 1994 to put into action a plan for the control and surveillance of multiresistant tuberculosis at a worldwide level (cfr. Guidelines for surveillance of drug resistance in tuberculosis WHO/TB/2003.320-WHO/CDS/RMD/2003.3). Among the strategies that have been developed against this serious problem which threatens worldwide health, is the development of new drugs to fight the types of strains involved.
Drugs for tuberculosis treatment are divided in “first line drugs” and “second line drugs”. The first line is of greatest effectiveness, and plays an indispensable role in primary therapeutic regimes to guarantee the treatment of this disease. Only four drugs make up the first group, which are: isoniazid, rifampicin, pyrazinamide, and ethambutol. The rest of the drugs nowadays available are included within the category of “second line drugs”.
For the treatment of multiresistant tuberculosis drug combinations are administered over prolonged periods of time. Nowadays, the choice treatment lasts six months and contemplates administration of a combination of isoniazid, rifampicin and pyrazinamide for two months, followed by the administration of isoniazid and rifampicin combination for four subsequent months. It is of vital importance to develop new drugs which permit reinforcement or improvement in the treatment of multiresistant tuberculosis.
On the other hand, related to the HIV epidemic and due to the generalized use in modern medicine of antitumour and immunosuppressor drugs, there have been increased infections produced by the named “atypical mycobacteria” (also known as “opportunist environmental mycobacteria” or as “nontuberculous mycobacteria”). This term includes numerous different species from whose method of transmission is not known, nor is their resistance mechanism to antimycobacterials. These atypical mycobacterias behave as microorganisms usually resistent to the drugs with antimycobaterial activity and pose a serious threat. From the numerous species isolated, Mycobacterium avium-intracellulare complex stands out for its frequency of producing serious disseminated infections and producing a pulmonar pathology undistinguishable from the one produced by M. tuberculosis. Mycobacterium avium-intracellulare complex behaves as multiresistant to the drugs of the “first” and “second line”. In the therapeutic regimes the rifabutin is generally the elective treatment, associated to a macrolide and to a quinolone. The high toxicity in vivo of the rifabutin represents a common inconvenience. Mycobacterium kansasii usually has a pattern of sensitivity much more variable, even though it exhibits resistance to isoniazid and ethambutol.
Rifamycins are natural chemical substances that were isolated for first time in 1959 from cultures of Nocardia Mediterranei as a complex mix of rifamycins A-E (cfr. P. Sensi et al., II Fármaco, Ed. Sc. 1959, vol. 14, pp. 146-147). They belong to the ansamycin family, antibiotics of great interest against Gram-positive bacteria and mycobacteria such as M. tuberculosis. They also have activity against the DNA-dependent bacterial RNA polymerase (cfr. C. Bartolucci et al., Fármaco 1992, vol. 47, p. 1367; C. Bartolucci et al., Pharm. Pharmacol. Lett, 1993, vol. 3, p. 1).
The structure of the rifamycins was determined by chemical degradation of the rifamycin S and by NMR spectroscopics studies. They present as common structural characteristic an aliphatic chain of 17 carbon atoms, called ansa, which connects two non adjacent positions of an aromatic plane chromophore core of naphtohydroquinone linked by an amide group.
The activity of these compounds is a consequence of the specific inhibition of the bacterial RNA polymerase through the formation of a very stable complex 1:1 between the drug and the enzyme, as it is shown in an investigation of the rifampicin. It has been proposed in a model in which the enzyme wraps the drug by the hydrophilic face and under the aromatic core, in such a way that the positions C3 and C4 do not participate in the joining. The studies of structure-activity relationship carried out with different rifamycins conclude that in order to maintain the inhibitory activity the following structural elements are necessary: a hydroxyl group or ketone in C1 and C8, hydroxyl groups in position C21 and C23, a determined spatial relation among the functional groups and an ansa bridge (cfr. P. Sensi, P. Appl. Chem. 1975, vol. 41, pp. 15-29).
Hundreds of semisynthetic rifamycins have been prepared with the hope of obtaining substances with better biological activities; most of them present modifications in the positions C4 (rifamide) and C3 (rifampicin). These structural changes do not affect the action of the substances over the enzyme in a critical way, but modify other important parameters such as the cellularcelular membrane permeability, the pharmacokinetic properties and the resortion (cfr. S. Lancini et al., “Structure-Activity Relationship among the Semisynthetic Antibiotics”. D. Perlmann, Ed., Academic Press, N.Y. 1977, pp. 531-600).
The spiropiperidylrifamycins are a class of semisynthetic antibiotics derived from the rifamycins in which the carbons C3 and C4 are incorporated into an imidazol ring, which itself has a spirocyclic piperidine (cfr. A. Sanfilippo et al., J. Antib. 1980, vol. 33, p. 1193; L. Marsili et al., J. Antib. 1981, vol. 34, p. 1033). The nitrogen atom from the piperidine ring may have different substituents (linear and ramificated alkyl radicals, functionalized alkyl, benzyl, acetyl and ethoxycarbonyl) (cfr. U.S. Pat. No. 4,086,225; DE 2,825,445-A). Among these spiropiperidylrifamycins, the rifabutin has been used with therapeutic purposes as a multidrug for the treatment of tuberculosis and against the Mycobacterium Avium-Mycobacterium intracellulare Complex (MAC) infections in patients with HIV (cfr. U.S. Pat. No. 4,219,478).
From what is known in the art, it is very desirable to provide new drugs possessing biological activity, not only against Mycobacterium tuberculosis, but also against mycobacterial infections in general.